Effect of a mutant form of I kappa B-alpha on 5-fluorouracil-induced apoptosis in transformed human salivary gland cells

Increasing evidence indicates that transcription factor NF-kappaB may play a role in cell survival, and that some chemotherapeutic agents activate NF- kappaB, while inhibition of NF-kappaB renders cells sensitive to these drug s. 5-Fluorouracil (5-FU) exerts its cytotoxic effect through the induction of apoptosis. However, it still remains uncertain whether 5-FU treatment in combination with the inhibition of NF-kappaB largely exerts an anti-prolif erative effect on the growth of neoplastic human salivary gland cells. Thus , we investigated whether NF-kappaB suppression in transformed human saliva ry gland (NS-SV-AC) cells leads to a marked reduction in cell growth in res ponse to 5-FU treatment. Our results demonstrated that under unstimulated c onditions, the ability of cell growth in the super-repressor form of I kapp aB-alpha (srI kappaB-alpha) cDNA-transfected cell clones (ACMT-6 and -7) wa s significantly lower than that in the empty vector-transfected cell clone (ACpRc-1). In addition, the growth inhibition caused by 5-FU was greatly en hanced in ACMT-6 and -7 as compared to ACpRc-1. Based on fractional inhibit ion analysis, this growth inhibition was due to an additive effect of both inhibitors. Electrophoretic mobility shift assay revealed that NF-kappaB ac tivity in these cell clones was not affected by treatment with 5-FU. Accord ingly, our data provide evidence that the combination of 5-FU and NF-KB sup pression cooperatively functions in the growth inhibition of NS-SV-AC cells . (C) 2001 Elsevier Science Ltd. All rights reserved.